This invention relates to methods and apparatus for correcting errors in the measured mass-to-charge ratios of ions determined by time-of-flight mass spectrometry, especially those due to the dead-time of an ion-counting detector.
In a time-of-flight mass spectrometer, bunches of ions are caused to enter a field-free drift region with essentially the same kinetic energy. In the drift region ions of different mass-to-charge ratios in each bunch travel with different velocities and therefore arrive at an ion detector disposed at the exit of the drift region at different times. Measurement of the ion transit-time therefore determines mass-to-charge ratio of that ion.
Currently, the ion detector most commonly employed in time-of-flight mass spectrometers is a single-ion counting detector which produces an electrical pulse signal in response to an ion impact on its detecting surface. In practice, such a detector may comprise one or more channelplate electron multipliers which produce a bunch of electrons in response to an ion impact. These electrons are collected on one or more collection electrodes which are connected to a charge-sensing discriminator. The discriminator generates an electrical signal in response to the electrons arriving at the collection electrode. The signal produced by the discriminator is used to determine the transit time of the ion which struck the detector, typically by means of a multistop time-to-digital converter which is started as a bunch of ions enters the drift region.
In order to acquire a complete mass spectrum, bunches of ions are repetitively generated from a sample and the transit times (as determined by the time-to-digital converter) of the detected ions are used to produce a histogram of the number of ion arrivals against mass-to-charge ratio. Typically, about 1,000 ion bunches may be analyzed to obtain a complete spectrum during a total time period of a few mS. The chief advantage of this form of time-of-flight mass spectroscopy is therefore that every ion which enters the drift region is in theory detected in contrast with scanning mass analyzers in which only a small proportion of the ions entering the analyzer can be detected in any instant. However, this theoretical advantage is only realised in practice if the ion bunches can be produced very quickly, otherwise a complete mass spectrum may take longer to acquire than it would with a scanning mass analyzer.
Partly for this reason, and also because of the limited mass resolution of prior types of time-of-flight mass spectrometers, time-of-flight mass analyzers have not been extensively used in organic mass spectroscopy until recently, despite their ability to analyze ions of very high mass-to-charge ratios. However, the availability of fast and cheap digital computers which are capable of processing the large quantity of data produced sufficiently quickly, and the development of techniques for improving resolution such as orthogonal acceleration time-of-flight mass spectrometers have resulted in time-of-flight mass spectrometers having become the analyzer of choice for high mass organic molecules.
As explained, in order to obtain maximum advantage from a time-of-flight analyzer in organic applications the ion detector must be capable of very fast operation. Typically, ion arrival times are recorded at 1 nS intervals, but in practice all detectors exhibit a certain dead-time following an ion impact during which the detector cannot respond to another ion impact A typical detector dead-time may be of the order of 5 ns and it is quite likely that during acquisition of a typical spectrum ions will arrive during detector dead-time and will consequently fail to be detected. As discussed below, failure to detect ions has a distorting effect on the resultant mass spectra which can only be avoided by reducing the rate at which ions reach the detector or by applying a dead-time correction. Particularly in the case of organic mass spectrometry, reducing the ion arrival rate is unacceptable for the reasons explained above, so that an effective and practical method of dead-time correction becomes very important.
The correction of dead-time for single-particle detectors or counters was first addressed by Schiff in Phys. Rev, 1936 vol 50 pp 88-96. Schiff assumed that the number of particles arriving at a detector in a given time-interval was governed by Poisson""s law and derived analytical expressions which allowed an observed count rate to be corrected once the counter dead-time had been determined. Since then there have been many publications which give expressions for dead-time correction for a variety of different detectors and experimental conditions. Coates (in J. Phys. E, 1968 vol 1 pp 878-, J. Phys. E. vol 5 pp 150- and Rev. Sci. Instrum 1972 vol 43 pp 1855-) and Donohue and Stern in Rev. Sci. Instrum. 1972 vol 43 pp 791-) describe analytical solutions of the problem of reconstructing the time distribution of detectors which have an extendable dead-time (that is, detectors wherein the arrival of a second particle during the dead-time already triggered by the earlier arrival of another particle causes that dead-time to extend).
Esposito et al, in Rev. Sci. Instrum. 1991 vol 62 (11) pp 2822- has extended this analysis to include the situation where more than one particle is expected to be detected in any one measurement cycle and for the more complicated case of detectors with non-extendable dead-times. Coates, in Rev. Sci. Instrum. 1992 vol 63 (3) pp 2084 -, points out that in most practical cases the corrections can be achieved using simpler formulae, and gives as an example a simulated time-of-flight mass spectrum corrected for dead-time distortions using an iterative procedure. Stephan, Zehnpfenning and Benninghoven, in J. Vac. Sci. Technol. A, 1994 vol 12 (2) pp 405- specifically discuss the correction of time-of-flight mass spectra for detector dead-time effects using a procedure similar to those suggested by Esposito et al and Coates et al.
In order to apply these prior methods to data representing a complete time-of-flight mass spectrum, bunches of ions are generated repetitively from a sample and allowed to enter the drift region. The ion transit times are determined and allocated to time channels so that after all the bunches have been generated, each time channel contains a count equivalent to the number of ions which had that particular transit time. The value of the count in each time channel is then corrected using the appropriate equation from the prior publications discussed above. It will be appreciated that the correction applied to the count in each channel is dependent on the counts contained in at least some of the earlier channels so that to correct the entire spectrum it is necessary to apply the correction equations to every channel in sequence. This requires that the raw data is stored to enable the corrections to be carried out before the spectral information can be processed and acquisition of the next spectrum can begin. Because the correction calculations require significant computational time, the correction process will limit the rate at which spectra can be acquired and processed, which as explained may seriously limit the usefulness of time-of-flight analysis for organic mass spectrometry. The only way in which this delay in starting the acquisition of the next spectrum can be avoided is by storing all the raw data in fast memory for subsequent processing, which is an equally unattractive option.
It is an objective, therefore, of the present invention to provide a method of correcting the distortion of a time-of-flight mass spectrum due to detector dead-time without the need to either store or process the acquired data immediately following acquisition. It is another object of the invention to provide a method of correcting the error in the mass-calibration of time-of-flight mass spectra which sometimes results from detector dead-time and in particular a method which can be applied once the data has been processed.
According to a first aspect of the present invention there is provided a method of correcting mass-spectral data.
In a preferred embodiment a method according to the invention further comprises applying a correction to said observed peak area to obtain a value of said peak area corrected for the effect of detector dead-time, said correction being obtained from said predetermined correction table which additionally comprises peak-area corrections for different values of said distribution function and said observed peak areas.
Further preferably, the predetermined peak-shape function used is a Gaussian function which represents the characteristic shape of a mass peak produced by the time-of-flight mass spectrometer if the detector dead-time was zero.
However, other peak-shape functions may be used.
In a practical spectrometer the peak shape may be different at different masses, so that in a broader aspect the invention may comprise using different peak shape functions selected according to the observed mass centroid.
In further preferred embodiments, time-of-flight data may be acquired and processed without dead-time correction to yield mass-spectral data in the form of ion counts vs transit time (that is, ion intensity vs mass-to-charge ratio). Using conventional mass-spectral data processing algorithms, this data may be further processed to recognize mass peaks and to determine observed mass centroids and peak areas of the peaks of interest. According to the invention, the dead-time correction is applied only to these two numbers, and the raw data representing the peak may be discarded once they have been obtained. A distribution function is then calculated for the mass peak to be corrected using the predetermined peak-shape function.
In the case of a Gaussian peak-shape function, the distribution function may conveniently be the standard deviation, which is related by a simple expression to the instrumental resolution at that particular mass, as explained below. A correction to the observed mass centroid (and optionally the observed peak area) is then obtained from the predetermined correction table for the calculated distribution function and observed mass centroid.
In still further preferred embodiments the correction table comprises a set of xe2x80x9cpagesxe2x80x9d, that is, two-dimensional tables, one for each of a plurality of values of the distribution function, each page giving the values of corrections to be applied to the observed mass centroid for particular values of the observed peak area.
Optionally, each page may also give corrections for the observed peak areas stored alongside the corrections for the mass centroid.
It will be appreciated that by using the method of the invention, dead-time corrections can be applied to the mass peaks of interest without the need to store large quantities of data or to apply time consuming dead-time corrections in real time. Conveniently, the correction table can be stored in digital memory while data is being acquired, but it is also within the scope of the invention to apply the dead-time corrections to previously acquired mass spectral data which has been stored only in the form of mass peak intensities vs mass-to-charge ratio. In this respect the method of the invention represents a major advance over prior methods of dead-time correction which require the raw data to have been stored.
The corrections contained in the correction table may be determined by predicting the effect of detector dead-time on a plurality of simulated mass peaks having the specified peak-shape function, for each of a range of values of distribution functions and peak areas. Thus the corrections may be generated by first generating a set of simulated distorted data from data points representing an undistorted peak having the desired peak shape function, mass centroid, and distribution function by considering in turn the effect of a given detector dead-time on each data point which makes up the undistorted peak, thereby constructing a simulated peak distorted by the effects of detector dead-time. Corrections to the mass centroid and peak area of the distorted peak (which represents a peak actually generated by the mass spectrometer) can then be established by comparing the simulated distorted and undistorted peaks. This process must of course be repeated for ranges of peak areas and distribution functions, and for different peak shape functions and detector dead-times, if necessary. Although the generation of the correction table is obviously a time-consuming process, it need only be carried out once in respect of any particular type of instrument and detector.
It will be further appreciated that the invention is not limited to use of a Gaussian peak-shape function, although this is suitable for most practical purposes. Any function appropriate to the spectrometer characteristics may be employed.
Further, in order to provide accurate correction where the shape of the mass peaks changes over the mass range of the spectrometer, different peak shape functions, each with its own correction table, can be used, the appropriate table being selected at correction time according to the observed mass centroid.
According to a second aspect of the invention there is provided a time-of-flight mass spectrometer having improved dead-time correction.
In another embodiment, a spectrometer according to the invention further comprises computational means for correcting at least one of said observed peak areas to obtain a value of said peak area corrected for the effect of detector dead-time, said correction being obtained from said predetermined correction table which additionally comprises peak-area corrections for different values of said distribution function and said observed peak areas.
In a practical spectrometer, each of said computational means comprises one or more digital computers running one or more digital computer programs, and the data comprised in said predetermined correction table is contained in the memory of said computer(s).
In another embodiment, means may be provided for storing the data consisting of the observed peak area and observed peak mass centroid above in computer-readable form (for example, on a disk) and means are provided for reading that stored data at any convenient time and processing it in accordance with the invention.
In still further preferred embodiments the means for generating bunches of ions may comprise either an electrospray or an APCI (Atmospheric Pressure Chemical Ionization) ion source, and the drift region may comprise a reflecting time-of-flight mass analyzer. Further preferably, the time-of-flight mass analyzer may be of the orthogonal acceleration type.